Jia Keren, Wu Yingcheng, Huang Jing, Chen Jianing, Wei Huagen, Wu Huiqun
School of Medicine, Nantong University, Nantong, Jiangsu 226001, P.R. China.
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China.
Oncol Lett. 2020 Aug;20(2):1866-1878. doi: 10.3892/ol.2020.11695. Epub 2020 Jun 5.
Invasive breast carcinoma (BRCA) is a serious disease that threatens the survival time of those affected. Alternative splicing (AS) involved in BRCA pathogenesis may be a potential therapeutic target. However, to the best of our knowledge, a systematic analysis of survival-related alternative splicing events (SREs) has not yet been reported. The aim of the present study was to identify SREs and analyze their potential biological functions as BRCA prognostic biomarkers. An UpSet plot demonstrated AS global characteristics. Cox's proportional hazards regression model quantitatively demonstrated the prognostic relevance of AS events. Functional enrichment analysis investigated the potential pathways through which AS events affect BRCA progression. The receiver operating characteristic curve model determined the clinical significance of AS events represented using percent-spliced-in (PSI) values. The regulatory network of splicing factors (SFs) and AS events laid the foundation for studying the role of SFs in BRCA. The present study identified 1,215 SREs and their distribution characteristics, suggesting that AS events in exon skipping (ES) primarily exerted normal physiological functions, while AS events in alternative terminator sites had the most significant prognostic effect. The present study demonstrated that survival-associated genes are involved primarily in certain biological processes of ribosomal proteins. In the diagnostic model, the alternative acceptor site, alternative donor site, alternative promoter site and ES performed well. ELAVL4 was the key gene associated with prognosis and SREs. In conclusion, a number of AS events affect BRCA initiation, progression and prognosis. The PSI value of AS events has the potential to diagnose BRCA and predict a prognosis; however, this must be confirmed in additional studies.
浸润性乳腺癌（BRCA）是一种严重疾病，会威胁患者的生存时间。参与BRCA发病机制的可变剪接（AS）可能是一个潜在的治疗靶点。然而，据我们所知，尚未有关于生存相关可变剪接事件（SRE）的系统分析报道。本研究的目的是识别SRE，并分析它们作为BRCA预后生物标志物的潜在生物学功能。一个UpSet图展示了AS的全局特征。Cox比例风险回归模型定量地证明了AS事件的预后相关性。功能富集分析研究了AS事件影响BRCA进展的潜在途径。受试者工作特征曲线模型确定了使用剪接百分率（PSI）值表示的AS事件的临床意义。剪接因子（SF）和AS事件的调控网络为研究SF在BRCA中的作用奠定了基础。本研究识别出1215个SRE及其分布特征，表明外显子跳跃（ES）中的AS事件主要发挥正常生理功能，而可变终止位点中的AS事件具有最显著的预后影响。本研究表明，生存相关基因主要参与核糖体蛋白的某些生物学过程。在诊断模型中，可变受体位点、可变供体位点、可变启动子位点和ES表现良好。ELAVL4是与预后和SRE相关的关键基因。总之，许多AS事件影响BRCA的发生、进展和预后。AS事件的PSI值有诊断BRCA和预测预后的潜力；然而，这必须在更多研究中得到证实。
